SummaryEach year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.

Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. The cellular and molecular basis of this enigmatic sense, known as magnetoreception, remains an unsolved scientific mystery. One hypothesis that attempts to explain the basis of this sensory faculty is known as the magnetite theory of magnetoreception. It argues that magnetic information is transduced into a neuronal impulse by employing the iron oxide magnetite (Fe3O4). Current evidence indicates that pigeons employ a magnetoreceptor that is associated with the ophthalmic branch of the trigeminal nerve and the vestibular system, but the sensory cells remain undiscovered. The goal of this ambitious proposal is to discover the cells and molecules that mediate magnetoreception. This overall objective can be divided into three specific aims: (1) the identification of putative magnetoreceptive cells (PMCs); (2) the cellular characterisation of PMCs; and (3) the discovery and functional ablation of molecules specific to PMCs. In tackling these three aims this proposal adopts a reductionist mindset, employing and developing the latest imaging, subcellular, and molecular technologies.

SummaryRecent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.

Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.

Max ERC Funding

1 498 985 €

Duration

Start date: 2014-01-01, End date: 2018-12-31

Project acronymChromHeritance

ProjectChromosome inheritance from mammalian oocytes to embryos

Researcher (PI)Kikue Tachibana-Konwalski

Host Institution (HI)INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH

Call DetailsStarting Grant (StG), LS3, ERC-2013-StG

SummaryOne of the most dramatic transitions in biology is the oocyte-to-zygote transition. This refers to the maturation of the female germ cell or oocyte, which undergoes two rounds of meiotic chromosome segregation and, following fertilization, is converted to a mitotically dividing embryo. We aim to establish an innovative research program that addresses fundamental questions about the molecular processes controlling the mammalian oocyte-to-zygote transition to ensure faithful inheritance of genomes from one generation to the next. We are taking an interdisciplinary approach combining germ cell and chromosome biology with cell cycle and epigenetic studies to understand how maternal factors regulate chromosome segregation in oocytes and chromatin organization in the zygote. A molecular understanding of key players regulating these processes is a requisite step for investigating how their deterioration contributes to maternal age-related aneuploidy and infertility. Aneuploidy is the leading cause of mental retardation and spontaneous miscarriage. The current trend towards advanced maternal age has increased the frequency of trisomic fetuses by 71% in the past ten years. A better understanding of mammalian meiosis is therefore relevant to human reproductive health.
A special feature of the female germ line is that meiotic DNA replication occurs in the embryo but oocytes remain arrested until the first meiotic division is triggered months (mouse) or decades (human) later. The longevity of oocytes poses a challenge for the cohesin complex that must hold together sister chromatids from DNA synthesis until chromosome segregation. We specifically aim to: 1) elucidate how sister chromatid cohesion is maintained in mammalian oocytes, 2) identify mechanisms regulating cohesion in young and aged oocytes, and 3) investigate how the inheritance of genetic and resetting of epigenetic information is coordinated with cell cycle progression at the oocyte-to-zygote transition.

One of the most dramatic transitions in biology is the oocyte-to-zygote transition. This refers to the maturation of the female germ cell or oocyte, which undergoes two rounds of meiotic chromosome segregation and, following fertilization, is converted to a mitotically dividing embryo. We aim to establish an innovative research program that addresses fundamental questions about the molecular processes controlling the mammalian oocyte-to-zygote transition to ensure faithful inheritance of genomes from one generation to the next. We are taking an interdisciplinary approach combining germ cell and chromosome biology with cell cycle and epigenetic studies to understand how maternal factors regulate chromosome segregation in oocytes and chromatin organization in the zygote. A molecular understanding of key players regulating these processes is a requisite step for investigating how their deterioration contributes to maternal age-related aneuploidy and infertility. Aneuploidy is the leading cause of mental retardation and spontaneous miscarriage. The current trend towards advanced maternal age has increased the frequency of trisomic fetuses by 71% in the past ten years. A better understanding of mammalian meiosis is therefore relevant to human reproductive health.
A special feature of the female germ line is that meiotic DNA replication occurs in the embryo but oocytes remain arrested until the first meiotic division is triggered months (mouse) or decades (human) later. The longevity of oocytes poses a challenge for the cohesin complex that must hold together sister chromatids from DNA synthesis until chromosome segregation. We specifically aim to: 1) elucidate how sister chromatid cohesion is maintained in mammalian oocytes, 2) identify mechanisms regulating cohesion in young and aged oocytes, and 3) investigate how the inheritance of genetic and resetting of epigenetic information is coordinated with cell cycle progression at the oocyte-to-zygote transition.

Max ERC Funding

1 499 738 €

Duration

Start date: 2014-02-01, End date: 2019-01-31

Project acronymCrowdLand

ProjectHarnessing the power of crowdsourcing to improve land cover and land-use information

SummaryInformation about land cover, land use and the change over time is used for a wide range of applications such as nature protection and biodiversity, forest and water management, urban and transport planning, natural hazard prevention and mitigation, agricultural policies and monitoring climate change. Furthermore, high quality spatially explicit information on land cover change is an essential input variable to land use change modelling, which is increasingly being used to better understand the potential impact of certain policies. The amount of observed land cover change also serves as an important indicator of how well different regional, national and European policies have been implemented.
However, outside Europe and outside the developed world in particular, information on land cover and land cover change in poorer countries is hardly available and no national or regional dense sample based monitoring approaches such as LUCAS exists which deliver sufficiently accurate land cover and land cover change information. Moreover in particular in developing countries, there is no or very little information on land-use and crop management. Only very limited data available from FAO and an incomplete coverage of sub-national statistics (e.g. IFPRI) are available.
This research project will assess the potential of using crowdsourcing to close these big data gaps in developing and developed countries with a number of case studies and different data collection methods. The CrowdLand project will be carried out in two very different environments, i.e. Austria and Kenya.The overall research objectives of this project are to 1) test the potential of using social gaming to collect land use information 2) test the potential of using mobile money to collect data in developing countries 3) understand the data quality collected via crowdsourcing 4) apply advanced methods to filter crowdsourced data in order to attain improved accuracy.

Information about land cover, land use and the change over time is used for a wide range of applications such as nature protection and biodiversity, forest and water management, urban and transport planning, natural hazard prevention and mitigation, agricultural policies and monitoring climate change. Furthermore, high quality spatially explicit information on land cover change is an essential input variable to land use change modelling, which is increasingly being used to better understand the potential impact of certain policies. The amount of observed land cover change also serves as an important indicator of how well different regional, national and European policies have been implemented.
However, outside Europe and outside the developed world in particular, information on land cover and land cover change in poorer countries is hardly available and no national or regional dense sample based monitoring approaches such as LUCAS exists which deliver sufficiently accurate land cover and land cover change information. Moreover in particular in developing countries, there is no or very little information on land-use and crop management. Only very limited data available from FAO and an incomplete coverage of sub-national statistics (e.g. IFPRI) are available.
This research project will assess the potential of using crowdsourcing to close these big data gaps in developing and developed countries with a number of case studies and different data collection methods. The CrowdLand project will be carried out in two very different environments, i.e. Austria and Kenya.The overall research objectives of this project are to 1) test the potential of using social gaming to collect land use information 2) test the potential of using mobile money to collect data in developing countries 3) understand the data quality collected via crowdsourcing 4) apply advanced methods to filter crowdsourced data in order to attain improved accuracy.

Max ERC Funding

1 397 200 €

Duration

Start date: 2014-04-01, End date: 2019-03-31

Project acronymDOiCV

ProjectDiscrete Optimization in Computer Vision: Theory and Practice

Researcher (PI)Vladimir Kolmogorov

Host Institution (HI)INSTITUTE OF SCIENCE AND TECHNOLOGYAUSTRIA

Call DetailsConsolidator Grant (CoG), PE6, ERC-2013-CoG

SummaryThis proposal aims at developing new inference algorithms for graphical models with discrete variables, with a focus on the MAP estimation task. MAP estimation algorithms such as graph cuts have transformed computer vision in the last decade; they are now routinely used and are also utilized in commercial systems.
Topics of this project fall into 3 categories.
Theoretically-oriented: Graph cut techniques come from combinatorial optimization. They can minimize a certain class of functions, namely submodular functions with unary and pairwise terms. Larger classes of functions can be minimized in polynomial time. A complete characterization of such classes has been established. They include k-submodular functions for an integer k _ 1.
I investigate whether such tools from discrete optimization can lead to more efficient inference algorithms for practical problems. I have already found an important application of k-submodular functions for minimizing Potts energy functions that are frequently used in computer vision. The concept of submodularity also recently appeared in the context of the task of computing marginals in graphical models, here discrete optimization tools could be used.
Practically-oriented: Modern techniques such as graph cuts and tree-reweighted message passing give excellent results for some graphical models such as with the Potts energies. However, they fail for more complicated models. I aim to develop new tools for tackling such hard energies. This will include exploring tighter convex relaxations of the problem.
Applications, sequence tagging problems: Recently, we developed new algorithms for inference in pattern-based Conditional Random Fields (CRFs) on a chain. This model can naturally be applied to sequence tagging problems; it generalizes the popular CRF model by giving it more flexibility. I will investigate (i) applications to specific tasks, such as the protein secondary structure prediction, and (ii) ways to extend the model.

This proposal aims at developing new inference algorithms for graphical models with discrete variables, with a focus on the MAP estimation task. MAP estimation algorithms such as graph cuts have transformed computer vision in the last decade; they are now routinely used and are also utilized in commercial systems.
Topics of this project fall into 3 categories.
Theoretically-oriented: Graph cut techniques come from combinatorial optimization. They can minimize a certain class of functions, namely submodular functions with unary and pairwise terms. Larger classes of functions can be minimized in polynomial time. A complete characterization of such classes has been established. They include k-submodular functions for an integer k _ 1.
I investigate whether such tools from discrete optimization can lead to more efficient inference algorithms for practical problems. I have already found an important application of k-submodular functions for minimizing Potts energy functions that are frequently used in computer vision. The concept of submodularity also recently appeared in the context of the task of computing marginals in graphical models, here discrete optimization tools could be used.
Practically-oriented: Modern techniques such as graph cuts and tree-reweighted message passing give excellent results for some graphical models such as with the Potts energies. However, they fail for more complicated models. I aim to develop new tools for tackling such hard energies. This will include exploring tighter convex relaxations of the problem.
Applications, sequence tagging problems: Recently, we developed new algorithms for inference in pattern-based Conditional Random Fields (CRFs) on a chain. This model can naturally be applied to sequence tagging problems; it generalizes the popular CRF model by giving it more flexibility. I will investigate (i) applications to specific tasks, such as the protein secondary structure prediction, and (ii) ways to extend the model.

Summary"Our existence as human beings is based on plants and their products. Worldwide, crops are threatened by pests including biotrophic fungi. Therefore, it is of vital interest to develop new strategies to reduce crop losses and to improve crop plants for the growing world population. Biotrophic plant pathogens employ small secreted molecules, so-called effectors, to overcome plant defence systems and to establish biotrophy. The rapid increase in available genome sequences of biotrophic pathogens and in transcriptomic datasets of their biotrophic stages allow us to identify putative secreted proteinaceous effectors by bioinformatic means. However, our insight into the functions of these effectors is still very limited. In this proposal, the PI´s extensive experience on both the plant host side and the fungal pathogen side of the biotrophic interaction is exploited to develop a workflow for functional, partially robotic-based screens to fill this gap. The combination of screen-deduced functional information with the analysis of effector localisation and specific host interactors will provide the basis for formulating starting hypotheses of effector function. These will then be tested in individual case studies, employing the well established Ustilago maydis-Zea mays as well as the new Ustilago bromivora-Brachypodium distachyon model systems. The project will be conducted at the Max Planck Institute (MPI) for Terrestrial Microbiology in a highly stimulating scientific environment. Linking the dramatic morphological changes and underlying molecular events during biotrophy on the host side to the action of subsets or even single effector proteins will allow the creation of a synthetic effectome. The deep functional understanding of the manipulative toolbox of biotrophs has the potential to facilitate transgenic crop development and will open a new era in the development of sustainable antifungal plant protection strategies."

"Our existence as human beings is based on plants and their products. Worldwide, crops are threatened by pests including biotrophic fungi. Therefore, it is of vital interest to develop new strategies to reduce crop losses and to improve crop plants for the growing world population. Biotrophic plant pathogens employ small secreted molecules, so-called effectors, to overcome plant defence systems and to establish biotrophy. The rapid increase in available genome sequences of biotrophic pathogens and in transcriptomic datasets of their biotrophic stages allow us to identify putative secreted proteinaceous effectors by bioinformatic means. However, our insight into the functions of these effectors is still very limited. In this proposal, the PI´s extensive experience on both the plant host side and the fungal pathogen side of the biotrophic interaction is exploited to develop a workflow for functional, partially robotic-based screens to fill this gap. The combination of screen-deduced functional information with the analysis of effector localisation and specific host interactors will provide the basis for formulating starting hypotheses of effector function. These will then be tested in individual case studies, employing the well established Ustilago maydis-Zea mays as well as the new Ustilago bromivora-Brachypodium distachyon model systems. The project will be conducted at the Max Planck Institute (MPI) for Terrestrial Microbiology in a highly stimulating scientific environment. Linking the dramatic morphological changes and underlying molecular events during biotrophy on the host side to the action of subsets or even single effector proteins will allow the creation of a synthetic effectome. The deep functional understanding of the manipulative toolbox of biotrophs has the potential to facilitate transgenic crop development and will open a new era in the development of sustainable antifungal plant protection strategies."

Max ERC Funding

1 446 316 €

Duration

Start date: 2014-02-01, End date: 2019-01-31

Project acronymEINME

ProjectSystematic investigation of epistasis in molecular evolution

Researcher (PI)Fyodor Kondrashov

Host Institution (HI)INSTITUTE OF SCIENCE AND TECHNOLOGYAUSTRIA

Call DetailsStarting Grant (StG), LS2, ERC-2013-StG

SummaryWhy does a mutation have a deleterious effect when it occurs in one species but shows no apparent consequences on the phenotype when it occurs in another species? What are some of possible explanations on the molecular basis of this phenomenon? Are the computational predictions of the extent of this phenomenon in nature accurate? The present project aims to take a swing at answering, at least partially, these basic questions of epistasis in molecular evolution. Within our work we plan to address these issues using computational approaches, systematic fitness assays of engineered orthologous genotypes and experimental functional assays of specific cases of epistasis identified by evolutionary analysis. By tackling these goals and utilising this array of approaches the projects aims to create a synthesis between theory and experimentation under the confines of a single laboratory that will allow us to study this phenomenon in a systematic fashion on the interface of different fields and methodologies.

Why does a mutation have a deleterious effect when it occurs in one species but shows no apparent consequences on the phenotype when it occurs in another species? What are some of possible explanations on the molecular basis of this phenomenon? Are the computational predictions of the extent of this phenomenon in nature accurate? The present project aims to take a swing at answering, at least partially, these basic questions of epistasis in molecular evolution. Within our work we plan to address these issues using computational approaches, systematic fitness assays of engineered orthologous genotypes and experimental functional assays of specific cases of epistasis identified by evolutionary analysis. By tackling these goals and utilising this array of approaches the projects aims to create a synthesis between theory and experimentation under the confines of a single laboratory that will allow us to study this phenomenon in a systematic fashion on the interface of different fields and methodologies.

Max ERC Funding

1 461 576 €

Duration

Start date: 2014-01-01, End date: 2018-12-31

Project acronymGENDERC

ProjectGendered dimensions in ERC grant selection – gendERC

Host Institution (HI)JOANNEUM RESEARCH FORSCHUNGSGESELLSCHAFT MBH

Call DetailsSupport Actions (SA), ERC-2013-Support-1

SummaryThe project will analyze the ERC practices and processes in the contect of gender mainstreaming especially during submission of proposals and in peer review processes. The main objective of this project is to identify and analyze gender biases related to different stages of the application and evaluation process within the ERC. Avoiding gender biases is essential to guarantee excellence and gender fairness. Therefore we will review official ERC documents, analyze the selection procedures and practices for reviewers and to study the mechanisms and practices related to peer review processes. For this purpose it is necessary to apply a set of different qualitative and quantitative methods and to assemble a research consortium which comprises the specific competences and resources needed. The results will be delivered and presented in form which allows to feed them into the strategic orientations of the Scientific Council and to apply them to the ERC´s operations.In this project, we investigate the extent and sources of gender bias in grant reviewing schemes, using ERC Starting Grants and Advanced Grants as case studies. The project focuses on the three main aspects of the schemes: the formal requirements and procedures, the composition of the reviewers and panels, and the process of application and evaluation. More specifically the following questions are answered: (i) Does the application process lead to gendered self-selection? (ii) Where in the selection process are (potentially) gender-biased decisions made? (iii) Are the decision criteria gender-biased, and/or are they deployed in a gender-biased manner? (iv) To what extent is this due to the (gender or topical biased) composition of the panels and/or reviewers?

The project will analyze the ERC practices and processes in the contect of gender mainstreaming especially during submission of proposals and in peer review processes. The main objective of this project is to identify and analyze gender biases related to different stages of the application and evaluation process within the ERC. Avoiding gender biases is essential to guarantee excellence and gender fairness. Therefore we will review official ERC documents, analyze the selection procedures and practices for reviewers and to study the mechanisms and practices related to peer review processes. For this purpose it is necessary to apply a set of different qualitative and quantitative methods and to assemble a research consortium which comprises the specific competences and resources needed. The results will be delivered and presented in form which allows to feed them into the strategic orientations of the Scientific Council and to apply them to the ERC´s operations.In this project, we investigate the extent and sources of gender bias in grant reviewing schemes, using ERC Starting Grants and Advanced Grants as case studies. The project focuses on the three main aspects of the schemes: the formal requirements and procedures, the composition of the reviewers and panels, and the process of application and evaluation. More specifically the following questions are answered: (i) Does the application process lead to gendered self-selection? (ii) Where in the selection process are (potentially) gender-biased decisions made? (iii) Are the decision criteria gender-biased, and/or are they deployed in a gender-biased manner? (iv) To what extent is this due to the (gender or topical biased) composition of the panels and/or reviewers?

Max ERC Funding

200 000 €

Duration

Start date: 2014-04-01, End date: 2016-02-29

Project acronymGRAPHALGAPP

ProjectChallenges in Graph Algorithms with Applications

Researcher (PI)Monika Hildegard Henzinger

Host Institution (HI)UNIVERSITAT WIEN

Call DetailsAdvanced Grant (AdG), PE6, ERC-2013-ADG

SummaryThis project has two thrusts of equal importance. Firstly, it aims to develop new graph algorithmic techniques, specifically in the areas of dynamic graph algorithms, online algorithms and approximation algorithms for graph-based optimization problems. Thus, it proposes to solve long-standing, fundamental problems that are central to the field of algorithms. Secondly, it plans to apply these techniques to graph algorithmic problems in different fields of application, specifically in computer-aided verification, computational biology, and web-based advertisement with the goal of significantly advancing the state-of-the-art in these fields. This includes theoretical work as well as experimental evaluation on real-life data sets.
Thus, the goal of this project is a comprehensive approach to algorithms research which involves both excellent fundamental algorithms research as well as solving concrete applications.

This project has two thrusts of equal importance. Firstly, it aims to develop new graph algorithmic techniques, specifically in the areas of dynamic graph algorithms, online algorithms and approximation algorithms for graph-based optimization problems. Thus, it proposes to solve long-standing, fundamental problems that are central to the field of algorithms. Secondly, it plans to apply these techniques to graph algorithmic problems in different fields of application, specifically in computer-aided verification, computational biology, and web-based advertisement with the goal of significantly advancing the state-of-the-art in these fields. This includes theoretical work as well as experimental evaluation on real-life data sets.
Thus, the goal of this project is a comprehensive approach to algorithms research which involves both excellent fundamental algorithms research as well as solving concrete applications.

Max ERC Funding

2 428 258 €

Duration

Start date: 2014-03-01, End date: 2019-08-31

Project acronymHAPLOID

Project“Yeast” genetics in mammalian cells to identify fundamental mechanisms of physiology and pathophysiology

Researcher (PI)Josef Penninger

Host Institution (HI)INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH

Call DetailsAdvanced Grant (AdG), LS4, ERC-2013-ADG

Summary"Some organisms such as yeast or social insects are haploid, i.e. they carry a single set of chromosomes. Organisms with a single copy of their genome provide a basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Recessive genetic screens have markedly contributed to our understanding of normal development, basic physiology, and disease. However, all somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure mutational screens. Although deemed impossible, we were able to develop generate mammalian haploid embryonic stem cells, thereby breaking a paradigm of biology.
Our novel stem opens the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. The following projects are proposed:
1. Towards“yeast” genetics in mammalian stem cells. Development of optimized technologies for rapid, genome-wide screens via repairable mutagenesis. Mutational bar-coding to introduce quantitative genomics to mammalian biology.
2. Forward genetic screens to uncover essential stem cell genes, identify novel stemness factors, develop improved systems for iPS cell derivation, and to perform synthetic lethal screens for anti-cancer drugs.
3. Reverse genetics using to identify and validate genes involved in cardiovascular physiology, brown and white fat cell development, and pain sensing.
4. Hit validation – exemplified by resistance to the bioweapon ricin.
Haploid embryonic stem cells carry the promise to revolutionize functional genetics and allow rapid, near whole genome-wide mutational forward genetics analysis and reverse genetics in defined cell types. Our systems will be made available to all researchers and the knowledge gained from our studies should fundamentally impact on the basic understanding of physiology and disease pathogenesis."

"Some organisms such as yeast or social insects are haploid, i.e. they carry a single set of chromosomes. Organisms with a single copy of their genome provide a basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Recessive genetic screens have markedly contributed to our understanding of normal development, basic physiology, and disease. However, all somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure mutational screens. Although deemed impossible, we were able to develop generate mammalian haploid embryonic stem cells, thereby breaking a paradigm of biology.
Our novel stem opens the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. The following projects are proposed:
1. Towards“yeast” genetics in mammalian stem cells. Development of optimized technologies for rapid, genome-wide screens via repairable mutagenesis. Mutational bar-coding to introduce quantitative genomics to mammalian biology.
2. Forward genetic screens to uncover essential stem cell genes, identify novel stemness factors, develop improved systems for iPS cell derivation, and to perform synthetic lethal screens for anti-cancer drugs.
3. Reverse genetics using to identify and validate genes involved in cardiovascular physiology, brown and white fat cell development, and pain sensing.
4. Hit validation – exemplified by resistance to the bioweapon ricin.
Haploid embryonic stem cells carry the promise to revolutionize functional genetics and allow rapid, near whole genome-wide mutational forward genetics analysis and reverse genetics in defined cell types. Our systems will be made available to all researchers and the knowledge gained from our studies should fundamentally impact on the basic understanding of physiology and disease pathogenesis."